Immunotherapy that improves response to chemotherapy in high-grade serous ovarian cancer

Samar Elorbany (), Chiara Berlato, Larissa S. Carnevalli, Eleni Maniati, Simon T. Barry, Jun Wang, Ranjit Manchanda, Julia Kzhyshkowska and Frances Balkwill
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Samar Elorbany: Charterhouse Square
Chiara Berlato: Charterhouse Square
Larissa S. Carnevalli: AstraZeneca
Eleni Maniati: Charterhouse Square
Simon T. Barry: AstraZeneca
Jun Wang: Charterhouse Square
Ranjit Manchanda: Queen Mary University of London
Julia Kzhyshkowska: Heidelberg University
Frances Balkwill: Charterhouse Square

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract Single-cell RNA sequencing (scRNAseq) of tumour-infiltrating immune cells in high-grade serous ovarian cancer (HGSOC) omental biopsies reveals potential targets that could enhance response to neo-adjuvant chemotherapy (NACT). Analysis of 64,097 cells identifies NACT-induced overexpression of stabilin-1 (clever-1) on macrophages and FOXP3 in Tregs that is confirmed at the protein level. STAB1 inhibition in vitro induces anti-tumour macrophages. FOXP3 anti-sense oligonucleotide (FOXP3-ASO), repolarises Tregs to an effector T cell phenotype. ScRNAseq on 69,781 cells from an HGSOC syngeneic mouse model recapitulates the patients’ data. Combining chemotherapy with anti-stabilin1 antibody and/or Foxp3-ASO significantly increases survival of mice with established peritoneal disease in two HGSOC syngeneic models and progression-free survival in a third model. Long-term survivors (300 days + ) are resistant to tumour rechallenge. Anti-stabilin1 antibody enriches the tumours with CXCL9+ macrophages and Foxp3-ASO increases TBET cell infiltration. Our results suggest that targeting these molecules in immune cells may improve chemotherapy response in patients.

Date: 2024
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DOI: 10.1038/s41467-024-54295-x

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